This competitive renewal is a series of 4 studies using the naloxone (NX) novel-response discrimination procedure in opioid-dependent humans that build upon our demonstration that this procedure can be used successfully as a model of opiate withdrawal (OW) to examine nonopioid mechanisms underlying this phenomenon. Previously, we showed that the opioid agonist hydromorphone blocks the effects of NX while the partial opioid agonists nalbuphine and butorphanol, and the alpha2-adrenergic (A2A) antagonist yohimbine produced NX-like effects. The relative efficacy of nonopioid compounds to attenuate the effects of NX were: Ca++ channel blocker (CCB) isradipine > A2A agonist clonidine => partial glycine agonist D- cycloserine >" NMDA antagonist dextromethorphan. This project will use the NX novel response discrimination procedure in opioid-dependent humans in order to do the following: 1) explore the efficacy of CCBs by testing the prototypic L-type agents (nifedipine, diltiazem, verapamil) as well as the N-type CCB gabapentin; 2) explore the efficacy of D-cycloserine at higher doses and examine the efficacy of the A2A agonist lofexidine; and 3) examine the efficacy of test compound combinations (e.g., lofexidine and isradipine) to attenuate the behavioral effects of NX. In the instructed novel response NX discrimination procedure, opioid-maintained subjects are trained to distinguish between NX (0.15 mg/70 kg) and placebo. Then effects of various agents are examined alone and combined with NX to determine whether they produce effects similar to either training condition or neither condition and alter NX's effects. This procedure allows for simultaneously assessing objective behavioral measures such as discrimination, self-reports and physiological responses, providing a wide behavioral profile of the OW phenomenon. The novel response procedure helps clarify interpretations of partial generalization and antagonism. This paradigm provides a sensitive, standard, objective, systematic method to identify potential agents for enhancing OW treatment which can be examined further in a detox protocol. [unreadable] [unreadable] [unreadable]